Increased activity of the hydrogen peroxide-producing enzyme monoamine oxidase B (MAO-B) and decreased levels of the peroxide-scavenging compound glutathione (GSH) have both been postulated to contribute to the selective demise of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD) via production of chronic oxidative stress in these cells. Oxidative stress may in turn impinge on mitochondrial function contributing to their subsequent neurodegeneration. Loss of mitochondria function in PD has been proposed to be the result of selective inhibition of mitochondrial complex I activity, however the specific cause or causes leading to its repression are unknown. We have recently demonstrated that subtle elevations in MAO-B or decreases in GSH in dopaminergic PC12 cells in vitro akin to that which occurs during brain aging or PD result in decreased mitochondriaI complex I activity. This appears to involve both direct oxidative damage to the complex itself as well as inhibition of the TCA enzyme alpha-ketoglutarate dehydrogenase (KDGH) which provides NADH as substrate to the complex. This in turn affects the capacity of the organelle to maintain function under stress conditions. As a logical extension of our published in vitro studies, we propose to analyze mitochondrial function and neurodegeneration in transgenic mouse lines created in our laboratory which possess inducibly increased levels of glial MAO-B mimicking those which occur during aging or decreases in GSH such as occurs in PD. This will allow us to assess the effects of this phenomenon on dopaminergic neurons of the SN which undergo degeneration in PD in the context of aging and stress. The ability to induce these changes in our transgenic models will allow us to examine the consequences of elevation in the adult animal bypassing any confounding developmental effects in a dosage-dependent and reversible manner. By looking throughout the lifespan, we will be able to assess the role that aging itself plays in this process. Information gleaned through these studies will allow us to test in future therapeutic strategies to minimize the effects of these alterations on mitochondrial function as it relates to PD and associated neurodegeneration.